tbuckley/cabot-search huggingface dataset:
Disease outcomes by race in patients with high-risk triple negative breast cancer with residual disease after neoadjuvant chemotherapy: A post-hoc analysis of the EA1131 randomized clinical trial.
Authors: Olga Kantor, Lisa A. Newman, Lauren K Anderson, Charity Glass, Erica L. Mayer, Esther R. Ogayo, Mariana Chavez-MacGregor, Rachel A. Freedman, Tari A. King, Elizabeth A. Mittendorf
Journal: Journal of Clinical Oncology (2023)

586 Background: Black women with breast cancer have the highest breast cancer mortality (BCM) rates of any racial and ethnic group. The higher burden of triple negative breast cancer (TNBC) in Black women contributes to disparities in BCM, but the extent to which disparate outcomes exist in patients with similar tumor biology is uncertain. The objective of this study was to examine racial differences in disease outcomes and BCM between Black and White patients in a clinical trial population of high-risk TNBC with residual disease after neoadjuvant chemotherapy (NAC). Methods: From 2015-2021, the ECOG-ACRIN EA1131 clinical trial randomized 415 clinical stage II-III TNBC patients with residual disease after NAC to either adjuvant capecitabine or platinum. For this analysis, 366 patients with known self-reported Black or White race and follow-up data were included. The aim of this unplanned exploratory analysis was to examine locoregional recurrence (LRR), distant recurrence (DR), and BCM by race using Kaplan-Meier curves for unadjusted estimates and Cox modeling for adjusted analyses. Results: Racial distribution of the analysis population included 66 (18.0%) Black and 300 (82.0%) White patients. 239 (65.3%) patients presented with clinical stage II and 127 (34.7%) with stage III disease. All patients had residual pathological disease after NAC: 86 (23.5%) stage I, 176 (48.1%) stage II, and 102 (27.9%) stage III (n=2 unknown). Median age was 49 years in Black and 54 years in White patients, p=0.003. Disease presentation, response to chemotherapy, and treatment arm were similar by race. Median follow up was 20 months. 2-year estimated LRR occurred in 31.6% of Black and 18.6% of White patients although this was not statistically significant (p=0.387), and 2-year estimated DR and BCM were similar by race. Estimated 2-year outcomes are outlined. Models adjusted for race, age, stage, grade, treatment arm, and locoregional therapy did not identify race as an independent predictor of LRR, DR, or BCM. Higher pathologic stage was the only consistent independent predictor of recurrent disease or BCM (stage III with HR 6.14 for LRR; HR 5.16 for DR; HR 6.84 for BCM; all p&lt;0.001). Conclusions: In this population of high-risk patients with residual TNBC after NAC with similar tumor biology treated on a clinical trial, there was a trend towards increased LRR in Black patients and similar DR and BCM between Black and White patients at 2 years of follow-up. This suggests that differences in BCM in other breast cancer populations may be at least partially driven by differences in tumor biology. Clinical trial information: NCT02445391 . [Table: see text]
Neoadjuvant giredestrant + palbociclib (P) vs. anastrozole (A) + P in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+, HER2– eBC): Patient (pt)-reported outcomes (PROs) in the randomized, open-label, international phase II coopERA BC study.
Authors: Yeon Hee Park, Vanesa Quiroga, Peter A. Fasching, Aditya Bardia, Vanesa López-Valverde, Tanja Badovinac Crnjevic, Jutta Steinseifer, Jacob Devine, Sara A. Hurvitz
Journal: Journal of Clinical Oncology (2023)

591 Background: Endocrine therapies (ETs) are the therapeutic mainstay for ER+ BC but persistent adverse events (AEs; eg joint pain, especially with aromatase inhibitors) negatively impact quality of life, and resistance impacts efficacy. Giredestrant, a highly potent, nonsteroidal, oral selective ER antagonist and degrader (PO SERD), may help address these issues. coopERA BC (NCT04436744) evaluated giredestrant in eBC and met its primary endpoint, demonstrating a greater reduction of Ki67 with giredestrant vs. A after 2 weeks. Giredestrant was well tolerated as a single agent and with P. We report exploratory PRO analyses. Methods: Pts with cT1c-cT4a-c (≥ 1.5 cm within cT1c) ER+, HER2– untreated eBC and baseline Ki67 score ≥ 5% were randomized 1:1 to 30 mg PO daily (QD) giredestrant or 1 mg PO QD A on days (D)1–14 of a window-of-opportunity phase. A 16-week neoadjuvant phase added 125 mg PO QD P on D1–21 of four 28-D cycles. Presence/frequency/severity/interference of relevant symptomatic AEs were assessed at Cycles 1–4 via NCI PRO-CTCAE library items; overall burden due to AEs, via FACT-G item GP5. Results: PRO completion rates were &gt; 80% at all time points. PRO-CTCAE postbaseline frequency scores were comparable between arms and mostly 0/1 (never/rare; reported for: Diarrhea &gt; 80% of pts; hot flash &gt; 60%; joint pain &gt; 65%; nausea &gt; 90%; vomiting &gt; 90%). No rash was reported by &gt; 90% of pts; fatigue at 0/1 severity (none/mild) by &gt; 75% and at 0/1 interference (none at all/a little bit) by 80%. Hot flash frequency scores of 2–4 (occasionally/frequently/almost constantly) were reported by 30% of pts in the giredestrant + P arm and 37% in the A + P arm; joint pain frequency scores of 2–4, by 25% and 35%. Worst postbaseline scores of 3–4 are shown in the table. FACT-G GP5 showed greater proportions of “improved/no change” responses in the giredestrant + P than the A + P arm at Cycles 2–4 (Cycle 2 75%; Cycle 3 71%; Cycle 4 68% vs. 62%; 66%; 53%), and smaller proportions of “worsened” responses (25%; 29%; 32% vs. 38%; 34%; 47%). Conclusions: This is the first analysis to our knowledge of PROs with a PO SERD in eBC; it showed that most pts reported minimal symptomatic AEs at frequency and severity levels that were generally numerically lower in the giredestrant + P than the A + P arm (particularly joint pain). Furthermore, there were numeric trends towards greater stability and improvement and less worsening of treatment burden in the giredestrant + P arm. Studies to further assess giredestrant’s clinical benefit are ongoing in the adjuvant setting. Clinical trial information: NCT04436744 . [Table: see text]
A smart clinical cohort selection system for clinical oncology research.
Authors: Amna Basharat, Muddassar Farooq
Journal: Journal of Clinical Oncology (2023)

e13613 Background: Cohort selection for specialized clinical trials is a cardinal pillar of the evidence-based medicine; however, it is the most difficult, complex, time consuming, and expensive step. Determining the efficacy of a new treatment (or intervention) requires finding eligible patients meeting the inclusion and exclusion criteria. In specialized scenarios, the complex criteria may even require researchers to do time consuming manual reviews and analyses of electronic health records (EHRs) to shortlist qualified patients. The major contribution of this research is a set of novel semantic models to build a cohort for clinical research by enabling semantic search over electronic health records represented as Knowledge graphs (KGs). Methods: We present the design of a novel cohort retrieval system, satisfying inclusion and exclusion criteria of an oncology clinical research study. Knowledge graphs and semantic models: We construct knowledge graphs (KGs) to interconnect different data sources, stored in a data-lake, and develop semantic models that enable semantic search over the processed data. We designed and constructed an oncology knowledge graph that enables semantics driven cohort selection. In addition, we have built a novel cohort retrieval system, satisfying the inclusion and exclusion criteria of an oncology clinical research study, that utilizes a semantics driven dynamic query engine to generate and execute cohort selection queries on heterogeneous EHR data. Results: We obtained real world oncology data of 21,000 oncology patients and then constructed knowledge graphs for five cancer types -- Colon (C18), Lung (C34), Breast (C50), prostate (C61), and Multiple Myeloma (C90). The cohort building scenarios are designed to represent a mix of criterion types and combinations including both inclusion and exclusion criteria, involving conjunctions, disjunctions and numeric ranges. Our cohort builder is evaluated against ten well known key competency scenarios. A team of experts validated the results of our cohort builder obtained against these competency scenarios by directly querying the graph. Our extensive evaluations demonstrate that the cohort builder searches with 100% accuracy the patients that match the criteria specified in all ten competencies. The average time to build the cohort on all graphs for these competencies is less than 10 seconds compared with that of days when patients are manually searched in EHR systems. Conclusions: Our query engine is not tightly coupled with the architecture of our data-lake; rather its architecture is flexible and can be easily integrated with other enterprise data-lakes or EMR systems. In future, we plan to scale the extent of inclusion and exclusion criteria to provide interoperability with existing clinical trial knowledge. We also aim to empirically evaluate the efficiency of cohort selection queries using a knowledge graph with classical database query approaches.
Association of pretreatment chest CT abnormalities with trastuzumab deruxtecan–associated pneumonitis.
Authors: Rachel Occhiogrosso Abelman, Zachary Hartley-Blossom, Geoffrey G. Fell, Phoebe Ryan, Erika Nakajima, Beverly Moy, Leif W. Ellisen, Aditya Bardia, Florian J. Fintelmann, Laura Spring
Journal: Journal of Clinical Oncology (2023)

1106 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate approved for HER2+ metastatic breast cancer (MBC) and HER2-low (IHC 1+ or 2+ with FISH-) MBC . Pneumonitis with T-DXd has been observed in 13.6% of patients (pts) on DESTINY-Breast 01 (including 2.2% fatal events) and 12.1% in pts on DESTINY-BREAST 04 (including 0.8% fatal events). There is an unmet need to determine if pts with baseline lung abnormalities are at increased risk for development of pneumonitis from T-DXd. Methods: This retrospective cohort study included all pts treated with T-DXd for MBC at an academic institution from 1/2020 to 2/2023 for more than 1 cycle (&gt;21 days). Outcomes were evaluated from treatment initiation until 2/1/2023. Two board-certified radiologists blinded to outcomes reviewed staging chest CTs performed before initiating T-DXd and graded each scan on 16 parenchymal abnormalities, including presence of interstitial lung abnormalities (ILA). Pneumonitis was retrospectively adjudicated by an independent oncologist using chart review and graded according to CTCAE v5.0 and compared to the treating physician’s assessment. The difference of proportions was analyzed with the Pearson Chi-Square test. Significance was declared at the 0.05 type I error threshold. Results: A total of 68 pts (median age 57.3 years) were included (30 = HER2+, 24 = HR+/HER2 low, 14 = TNBC/HER2 low). By independent assessment, 16 pts (23.5%) had grade 1 pneumonitis and 3 pts (4.4%) grade 2 pneumonitis. Median time from treatment initiation to pneumonitis was 83 days (range 35-266). By treating physician assessment, 5 pts (7.4%) developed grade 1 pneumonitis and 3 pts (4.4%) developed grade 2 pneumonitis. 16 of 68 pts (23.5%) had baseline ILA and 62 pts (91.2%) had at least one other parenchymal abnormality. As assessed by an independent oncologist, of pts with baseline ILA (N = 16), 12.5% developed T-DXd related pneumonitis, compared to 32.7% of pts without pre-existing ILA (N=52), p=0.16. There was no statistical difference in T-DXd related pneumonitis assessed by treating physician between pts with baseline ILA (2/16 patients, 12.5%) compared to pts without baseline ILA (7/52 pts, 13.5%), p=0.68. Conclusions: In this study, presence of baseline ILA was not associated with subsequent pneumonitis from T-DXd. Notably, the rate of independently assessed pneumonitis was higher than treatment-attributed pneumonitis as defined by the treating physician. Further research is needed to validate these findings and define predictors of treatment-associated pneumonitis. [Table: see text]
Selective avoidance of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with HER-2 positive/triple negative breast cancer: Prospective, multi-center, single-arm study (ASLAN).
Authors: Jai Min Ryu, Wonshik Han, Han-Byoel Lee, Sung Gwe Ahn, Hee Jeong Kim, Hyung Seok Park, Ji Soo Choi, Haeyoung Kim, Jeong Eon Lee
Journal: Journal of Clinical Oncology (2023)

TPS624 Background: According to advanced neoadjuvant chemotherapy (NACT), which dual HER2 blockage in HER2+ BC and adding carboplatin or immunotherapy in triple-negative breast cancer (TNBC) increased pathologic complete response (ypCR) rates up to 68% and 80%. Because ypCR patients showed better survival, the indications for NACT have expanded to early BC and the expected ypCR rate has increased. Therefore, it may be reasonable to consider omitting surgery in cases with excellent responses to NACT. Several recent retrospective studies and pilot prospective studies have reported axillary pathologic complete response (ApCR) is highly correlated with breast pathologic complete response (BpCR) in HER2+ or TNBC after NACT. The current report describes the design of omission of sentinel lymph node biopsy (SLNB) after NACT in HER2+ or TNBC patients with excellent response. Similarly, EUBREAST-01 (NCT04101851) study is ongoing omission of sentinel lymph node biopsy (SLNB) after NACT in HER2+/TNBC with radiologic complete remission and a BpCR. Methods: The ASLAN trial is a prospective, multicenter, single-arm, clinical study. Five tertiary care hospitals in South Korea are participating. Inclusion criteria: women aged 20-69; cT1-3N0-1M0; HER2+ or TNBC (defined by ER-negative (&lt; 10% positive cells in IHC) and PgR-negative (&lt; 10% positive cells in IHC)); expected complete remission at physical examination and radiological expected Tumor size ≤ 2cm or non-mass enhancement ≤ 4cm at breast MRI after standard NACT; planned breast conserving surgery (BCS) with whole-breast irradiation; ECOG performance status 0-1. Exclusion criteria: SLNB before NACT; previous axillary surgery; bilateral BC. Patients who are eligible proceed BCS. After BCS, patients who showed BpCR are enrolled with omission of SLNB. Patients with no BpCR proceed with routine axillary surgery. The assumption for acceptable 5-year RFS ≥84% is based on previous study findings. The calculated total case number for per- protocol analysis is N=178. Primary endpoint: 5-year recurrence free survival. Secondary endpoint: local recurrence free survival, breast cancer specific survival, overall survival, ipsilateral axillary recurrence interval, distant metastasis free survival, contralateral breast free survival, re-operation rate according to breast biopsy after NACT, adverse event, and quality of life. The first patient was enrolled on September 2021. Among 147 patients who screened, 106 patients have been enrolled in January 2022. We plan to complete the target accrual by December 2025. Clinical trial information: NCT04993625 .
Characterization of the immune microenvironment in matched primary and metastatic breast cancer lesions from the AURORA study: BIG 14-01.
Authors: Florentine Hilbers, David Venet, Elisa Agostinetto, Matteo Benelli, Angel Guerrero, Diogo Martins-Branco, Alice Raimbault, Danai Fimereli, Lorenzo Ferrando, Sara Sommariva, Chiara Biagioni, Marta Paoli, Arnau Llinas-Bertran, Maya Dadiani, Gabriele Zoppoli, Marija Balic, Joan Albanell, Sebastian Vosberg, Alexandre Irrthum, Roberto Salgado
Journal: Journal of Clinical Oncology (2023)

1009 Background: Immunotherapy benefit in patients with metastatic breast cancer (MBC) is limited to patients with triple negative breast cancer and PD-L1 expression in the tumor sample. Multi-omics characterization of the anti-cancer immune response in MBC could provide novel insights into the mechanisms behind immune response failure. Methods: The AURORA program (NCT02102165) enrolled patients with MBC who received at most one line of treatment in the metastatic setting. RNA sequencing was performed on primary and metastatic lesions. Stromal tumor infiltrating lymphocytes (sTIL) were scored in line with the International Immuno-Oncology Biomarker Working Group for Breast Cancer recommendations. T cell and B cell receptor (TCR and BCR) analysis was performed with MiXCR. Deconvolution of bulk RNA sequencing data was performed using xCell. ImmuneScore-normalized Relative Abundance metastasis/primary Ratios (RAR) of immune cell types were calculated. All comparisons between primary and metastatic lesions were performed on matched samples. Wilcoxon signed-rank tests were used. Results: As expected, sTILs decreased from primary to metastatic lesion. However, 9% of metastatic lesions still had ⪰20% sTILs. Matched RNA expression data was available for 204 patients. Relative abundance of macrophages (RAR 3.3, p&lt;0.001) and Th1 cells (RAR 1.5, p&lt;0.001) was increased in the metastases, while Treg cells (RAR 0.12, p&lt;0.001), CD8+ T cells (RAR 0.32, p&lt;0.001) and B cells (RAR 0.32, p&lt;0.001) decreased the strongest. Metastases with ⪰20% sTILs had higher Treg cells (p&lt;0.001) and B cells (p&lt;0.001) compared to metastases with low sTILs, which had more Th1 cells (p&lt;0.001), mast cells (p&lt;0.001) and NKT cells (p&lt;0.001). De novo metastatic and synchronous primary samples had more BCR (p&lt;0.001) and TCR (p&lt;0.001) clones in common as compared to non-de novo metastatic cancers. Conclusions: sTIL percentage decreased from primary tumor to metastatic lesion. Metastatic lesions with many sTILs (⪰20%) were enriched for immune response suppressing regulatory T cells. [Table: see text]
Correlation of HER2 low status in I-SPY2 with molecular subtype, response, and survival.
Authors: Hope S. Rugo, Denise M. Wolf, Christina Yau, Emanuel Petricoin, Paula R Pohlmann, Lajos Pusztai, W. Fraser Fraser Symmans, Alexander Borowsky, Sandra Finestone, Douglas Yee, Nola Hylton, Laura van 't Veer, Laura Esserman, Angela DeMichele
Journal: Journal of Clinical Oncology (2023)

514 Background: HER2low, defined as immunohistochemical (IHC) 1+ or 2+ without HER2 gene amplification, predicted improved progression free and overall survival with trastuzumab deruxtecan (TDXd) compared to chemotherapy in patients (pts) with metastatic breast cancer in Destiny Breast04. Controversy exists regarding the correlation of HER2low with molecular subtypes and outcome. We evaluated these associations in the neoadjuvant ISPY2 trial. Methods: We investigated HER2 IHC class in pts with clinically HER2-negative breast cancer (BC) enrolled in the first 10 arms of ISPY2. To explore the biology of HER2low, we used Fisher’s exact test to assess association of IHC class (0 vs 1+ or 2+) with Response Predictive Subtypes-5 (RPS-5; based on immune, DNA repair damage (DRD), HER2, and luminal markers; PMID: 35623341), SET index [endocrine responsiveness], and Mammaprint high1 (MP1) vs high2 (MP2). Association with pathologic complete response (pCR) was assessed using Fisher’s exact test, and association with distant recurrence free survival (DRFS) was assessed using Cox Proportional Hazards modeling. Results: Of 742 HER2negative pts enrolled in the first 10 arms of ISPY2, local HER2 IHC is available for 585; 299 hormone receptor + (HR+) and 286 triple negative (TN). 63% of pts are HER2low, with HER2low status more frequent in HR+ (71%) compared to TN BC (55%; OR = 1.97; p = 0.00011). There was no clear relationship between HER2low IHC and RPS-5 subtypes or endocrine sensitivity measured by the SET index. There was no significant association of HER2low with pCR overall or within treatment arms (p &gt; 0.05); this was true for TN and HR+ subsets. 562 pts with HER2negative disease have distant recurrence free survival (DRFS) data with a median follow-up of 4.23 yrs. Pts with pCR had excellent outcome (5yr DRFS &gt; 94%), with no impact from HER2low vs 0 status. For pts with nonpCR, after adjusting for HR+ status, the DRFS hazard ratio for HER2low vs 0 status is not significant [0.68(0.46-1.02)]. Within HR+, HER2low is found in &gt; 70% for both SET low and high. HR+/MP1 pts (with generally low pCR rates) are significantly more likely to be HER2low (75%; (172/219)) compared to HR+/MP2 (61%; (49/80)) (OR: 1.79; Fisher p = 0.044). Importantly, 70% of HER2-Immune-/DRD- (78% HR+ and 56% TN), a subtype with low response to all ISPY2-tested agents, are HER2Low. Conclusions: In ISPY2 which enrolls patients with MP high risk BC, HER2low by IHC was frequent and higher in HR+ than TN disease. There was no clear association with molecular markers, pCR or DRFS. The frequency of HER2low in the immune-/DRD- subtype raises the potential for exploring T-DXd in this high risk, low-response setting. Clinical trial information: NCT01042379 .
Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers.
Authors: Sara P. Myers, Varadan Sevilimedu, Andrea Veronica Barrio, Audree Tadros, Anita Mamtani, Mark E. Robson, Monica Morrow, Minna Lee
Journal: Journal of Clinical Oncology (2023)

544 Background: Distinct pathological characteristics and mutational signatures in BRCA-associated breast cancers may result in differential response to chemotherapy but understanding of treatment response after neoadjuvant chemotherapy (NAC) is limited. We describe a single-institutional experience to compare rates of pathologic complete response (pCR) after NAC in BRCA carriers (g BRCA1/2) and noncarriers. Methods: From 11/2013 to 01/2022, 1426 consecutive women with clinical stage I-III breast cancer were treated with NAC followed by surgery. Baseline disease characteristics were compared between g BRCA1/2 and noncarriers using two-sample non-parametric tests. Conditional logistic regression was used to evaluate the association between BRCA status and pCR (i.e., ypT0/is pN0) adjusting for variables selected using backward elimination. Results: 92 (6.5%) and 73 (5.1%) had deleterious mutations in BRCA1 and BRCA2, respectively. Compared to noncarriers, g BRCA1/2 were younger (p&lt;0.001) with clinical T1 (p=0.002) and triple negative disease (TN) (57% vs 25% noncarriers, p&lt;0.001). Almost all patients received doxorubicin/cyclophosphamide/paclitaxel therapy (93%) with g BRCA1/2 more likely to receive carboplatin (p&lt;0.001). pCR rate was 42% of g BRCA1, 21% of g BRCA2, and 26% of noncarriers (p=0.001). Among clinically node positive (cN+) patients, nodal pCR was higher in g BRCA1/2 compared to noncarriers (53/96 (55%) vs 371/856 (43%), p=0.012). This difference was seen in ER+/HER2- (36% gBRCA1/2 vs 20% noncarriers; p=0.027) and TN subtypes (79% g BRCA1/2 vs 45% noncarriers; p&lt;0.001). Poorly differentiated tumors (p&lt;0.001), cN+ (p=0.010), lower cT stage (p=0.028), ductal histology (p&lt;0.001), TN and HER2+ receptor status (p&lt;0.001), absence of lymphovascular invasion (p&lt;0.001), carboplatin receipt (p=0.041), and BRCA1 status (p=0.001) were also associated with pCR on univariate analysis. After adjusting for differentiation and molecular subtype, BRCA1 status remained independently associated with pCR. Conclusions: g BRCA1 undergoing NAC have higher pCR rates relative to g BRCA2 and patients with sporadic disease. Across breast cancer subtypes, g BRCA1/2 more frequently converted to pN0. Defining biological mechanism for these findings would allow customization of treatment based on germline genetics. [Table: see text]